The need for safe and effective therapeutic agents for highly pathogenic agents is a key to the national biodefense. On the top of these pathogenic agents is Orthopoxvirus, including smallpox, monkeypox, cowpox and vaccinia virus. As smallpox virus is highly contagious by aerosol and the fatality is high, using these viruses for bioterrorism is highly probable. Particularly, the young generation is vulnerable as the virus has been officially eradicated in 1977 and no vaccination has been performed since then. Thus, in this application the major focus will be directed toward the discovery of antivirai agents for Orthopoxvirus based on our preliminary findings. In this regard, we recently discovered interesting carbocyclic nucleosides with potent anti-Orthopox virus activity in collaboration with investigators at the US Army Medical Research Institute for Infectious Diseases. Although these carbocyclic nucleosides are not the clinical candidates, they can serve as lead compounds for future chemical synthesis and biological evaluation. Additionally, Filoviruses, Category A agents (Ebola and Warburg virus) are highly contagious and create serious health crisis around the wodd, and therefore, their therapeutic intervention is part of the national biodefense plans. As the same carbocyclic nucleosides demonstrated interesting antiviral activity against Ebola virus, we will submit our proposed compounds to screen in our core laboratory (US Army Medical Research). Additionally, West Nile virus appears to have spread rapidly throughout the nation since it arrived in the US in 1999 and is has begun creating serious health problems in the US, and we definitely need safe and effective therapeutic agents. Again, series of carbocyclic nucleosides demonstrated interesting antiviral activity against West Nile virus, and therefore, we will continue to synthesize carbocyclic nucleosides for biological evaluation in collaboration with Dr. Robert Sidwell of Utah State University. We will also send the proposed compounds for antiviral evaluation against Hanta virus and other emerging virus if the screening systems become available in our collaborator's laboratories.